вход по аккаунту


Direct Magnesiation of Polyfunctionalized Arenes and Heteroarenes Using (tmp)2Mg2LiCl.

код для вставкиСкачать
DOI: 10.1002/anie.200701487
Synthetic Methods
Direct Magnesiation of Polyfunctionalized Arenes and Heteroarenes
Using (tmp)2Mg·2 LiCl**
Giuliano C. Clososki, Christoph J. Rohbogner, and Paul Knochel*
Dedicated to Professor Herbert Mayr on the occasion of his 60th birthay
Directed lithiations are important reactions for the functionalization of arenes and heterocycles.[1] In contrast, directed
magnesiation with magnesium bases has been used much less
often.[2] The pioneering work of Eaton et al.[3] demonstrated
the potential of this approach using magnesium bis(2,2,6,6tetramethylpiperamide), (tmp)2Mg. However, the limited
solubility of such bases in common organic solvents as well
as the requirement for an excess of the magnesium bases (2–
7 equiv) to achieve high conversions has precluded their
general use. Recently, we have reported that mixed Li/Mg
amides of the type R2NMgCl·LiCl and in particular
(tmp)MgCl·LiCl (1) are highly soluble magnesium bases
readily able to deprotonate a broad range of unsaturated
substrates.[4] However, some moderately activated arenes
such as tert-butyl benzoate (2 a) gave unsatisfactory results
(Scheme 1). Therefore, we have developed a new class of
mixed Li/Mg bases: magnesium bisamides complexed with
lithium chloride, (R2N)2Mg·2 LiCl (3). The reagents 3 a–c
were readily prepared by reacting R2NLi with MgCl2 in THF
Scheme 1. Comparison between magnesium amide 1 and magnesium
bisamides 3 a–c.
[*] Dr. G. C. Clososki, Dipl.-Chem. C. J. Rohbogner, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universit2t M3nchen
Butenandtstrasse 5–13, Haus F, 81377 M3nchen (Germany)
Fax: (+ 49) 89-2180-77680
[**] We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) for financial support. G.C.C.
thanks the Humboldt Foundation for a fellowship. We also thank
Chemetall GmbH (Frankfurt), Degussa GmbH (Hanau), and BASF
AG (Ludwigshafen) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under or from the author.
Angew. Chem. Int. Ed. 2007, 46, 7681 –7684
at 0 8C for 0.5 h. Whereas with (tmp)MgCl·LiCl no significant
deprotonation of 2 a was observed, the use of magnesium
bisamides complexed with two equivalents of LiCl such as
3 a–c led to excellent results (Scheme 1).
In general (tmp)2Mg·2 LiCl (3 a) proves to be the most
powerful and selective base,[5] and the best results were
obtained when it was freshly prepared. We have found that
this base can also be conveniently made by reacting
(tmp)MgCl·LiCl (1) with lithium 2,2,6,6-tetramethylpiperamide[6] for 30 min at 0 8C. Since 1 can be stored in THF at
25 8C for months, this alternative method appears to be the
best for routine experiments. Moreover, this procedure can
also be applied successfully for the preparation of 3 a in situ.
On the other hand, [tBu(iPr)N]2Mg·2 LiCl (3 c) can be stored
in THF at 4 8C for three weeks with no significant reduction of
A number of aromatic and heterocyclic substrates were
cleanly metalated with 3 a (Table 1). Thus, tert-butyl benzoate
(2 a) was converted to the ortho-magnesiated intermediate by
reaction with 3 a within 1 h at 25 8C. After transmetalation
with CuCN·2 LiCl,[7] the reaction with benzoyl chloride
provided the ketoester 4 b in 93 % yield (entry 1, Table 1).
Remarkably, the magnesiated intermediates of the type
ArMg(tmp)·2 LiCl obtained after the magnesiation with 3 a
were smoothly transmetalated with ZnCl2 (1.2 equiv) and
underwent a Negishi cross-coupling[8] with ethyl 4-iodobenzoate (1.5 equiv) in the presence of [Pd(dba)2] (2 mol %), and
P(o-furyl)3 (4 mol %) at 25 8C for 12 h, leading to the biphenyl
derivative 4 c in 82 % yield (entry 2, Table 1).
Similarly, the magnesiation of PhCO2iPr (2 b) with 3 a
(25 8C, 1 h) gave after copper(I)-mediated acylation with
propionyl chloride the ketone 4 d in 78 % yield (entry 3,
Table 1). Additionally, the reactions of 3 a and 3 c (1.2 equiv)
with ethyl naphthoate (2 c) led to the corresponding orthomagnesiated intermediates within 3 h at O 8C. Iodolysis,
bromolysis with (BrCl2C)2, or Negishi cross-coupling with 4iodo benzonitrile afforded the corresponding functionalized
derivatives 4 e–g in 81–83 % yield (entries 4–6, Table 1). The
presence of an electron-withdrawing group such as a bromine
substituent in the case of tert-butyl 4-bromobenzoate (2 d)
accelerated the metalation, furnishing the magnesiated product within 1 h at 20 8C. Quenching with iodine afforded tertbutyl 4-bromo-2-iodobenzoate (4 h) in 71 % yield (entry 7,
Table 1). A copper(I)-mediated benzoylation with benzoyl
chloride gave the corresponding tert-butyl 2-benzoyl-4-bromobenzoate (4 i) in 77 % yield (entry 8, Table 1). Although
benzonitriles are metalated sluggishly with 1, the use of 3 a
(1.2 equiv) led to a complete magnesiation of benzonitrile 2 f
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Table 1: Products of type 4 obtained by the magnesiation of arenes with (tmp)2Mg·2 LiCl (3 a) and reactions with electrophiles.
T [oC],t [h]
Yield [%][a]
2 a: R = tBu
2 a: R = tBu
2 b: R = iPr
25, 1
25, 1
25, 1
4 b: E = COPh, R = tBu
4 c: E = p-C6H4CO2Et, R = tBu
4 d: E = COEt, R = iPr
0, 3
0, 3
0, 3
4 e: E = I
4 f: E = Br
4 g: E = p-C6H4CN
20, 1
20, 1
4 h: E = I
4 i: E = COPh
30, 3
2 f: R = tBu,X = CH
2 f: R = tBu, X = CH
2 g: R = Et, X = N
2 g: R = Et, X = N
2 g: R = Et, X = N
0, 1
0, 1
40, 3
40, 3
40, 3
4 k: E = I, X = CH, R = tBu
4 l: E = p-IC6H4CO2Et,X = CH, R = tBu
4 m: E = I, X = N, R = Et
4 n: E = Br, X = N, R = Et
4 o: E = p-C6H4CN, X = N, R = Et
40, 12
[a] Yield of analytically pure product. [b] Transmetalation with CuCN·2 LiCl (0.2 mol %) was performed. [c] Obtained by palladium-catalyzed crosscoupling after transmetalation with ZnCl2 (1.2 to 1.3 equiv).
at 30 8C within 3 h. After Negishi cross-coupling with ethyl
4-iodobenzoate, the corresponding functionalized biphenyl
derivative 4 j was obtained in 70 % yield (entry 9, Table 1). A
1,3-diester such as 2 f was magnesiated regioselectively with
3 a in position 4 and not in position 2 as a result of steric
hindrance, providing after iodolysis or Negishi cross-coupling
reaction with ethyl 4-iodobenzoate the corresponding derivatives 4 k and 4 l in 94 % and 88 % yield, respectively
(entries 10 and 11, Table 1). The directed metalation of
pyridines is of great importance.[9] Ester-substituted pyridines
are also excellent substrates for base 3 a, and the diester 2 g
was converted to the corresponding 2-magnesiated pyridine
( 40 8C), which provided after iodolysis, bromolysis with
(BrCl2C)2, or Negishi cross-coupling with 4-iodobenzonitrile
the expected polyfunctional pyridines 4 m–o in 70–77 % yield
(entries 12–14, Table 1). Similarly 4-carbethoxypyridine (2 h)
reacted smoothly with 3 a ( 40 8C, 12 h) leading after
iodolysis to the 3-iodopyridine 4 p in 66 % yield (entry 15,
Table 1).
The new class of mixed Mg/Li bases of type 3 also
tolerates sensitive functional groups such as a ketone, a
carbonate (OBoc; Boc = tert-butoxycarbonyl), or a bis(dimethylamino) phosphonate group (OP(O)(NMe2)2). Thus, the
unsymmetrical benzophenone 5 bearing a Boc group as a
directing group was converted to the magnesiated intermediate 6 ( 20 8C, 4 h) leading, after a copper(I)-mediated
benzoylation with benzoyl chloride to the 1,2-diketone 7 in
72 % yield. Similarly, the Boc-protected ethyl benzoate 8 was
selectively converted to the magnesium intermediate 9 within
2 h at 0 8C, providing after iodolysis the corresponding 2iodobenzoate 10 in 78 % yield. The role of the Boc group is to
direct the magnesiation and to enhance the rate of metalation.
Interestingly, the powerful and more bulky bis(dimethylamino)phosphonate directing group allows a magnesiation of 11
within 1 h at 0 8C. Remarkably, the OP(O)(NMe)2 group
selectively directs the metalation to position 4 leading to the
magnesiated reagent 12 (Scheme 2). Quenching of 12 with I2
provided the aryl iodide 13 in 91 % yield.
The magnesiation of electron-rich aromatic rings is
especially difficult. However, such metalations can be performed successfully with the highly active bases of type 3. For
example, dimethyl-1,3-benzodioxan-4-one (14)[10] was converted to the corresponding magnesium reagent 15 within
10 min at 40 8C. After a transmetalation with ZnCl2 and Pdcatalyzed cross-coupling with (E)-1-hexenyl iodide[11] (16)
(1.5 equiv, 25 8C, 12 h), the 6-substituted benzodioxane (17)
was isolated in 77 % yield. Hydrogenation of the double bond
followed by cleavage of the dioxanone with excess of KOH
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7681 –7684
Scheme 2. Chemoselective directed magnesiation using 3 a.
provided the 6-hexylsalicylic acid (18), a natural product
found in the essential oil of Pelargonium sidoides DC,[12] in
89 % yield (Scheme 3).
nBuLi (2.4 m in Hexane, 12.5 mL, 30 mmol)
was added dropwise. After the addition was
complete, the reaction mixture was warmed
to 0 8C and stirred at this temperature for
30 min. Freshly titrated 1[4] (1.0 m in THF,
30 mL, 30 mmol) was then added dropwise to
the reaction mixture. The reaction mixture
was stirred at 0 8C for 30 min, warmed to
25 8C, and stirred for 1 h. The solvents were
then removed under vacuum affording a
yellowish solid. Freshly distilled THF was
then slowly added under vigorous stirring
until the salts were completely dissolved. The
resulting solution of 3 a solution was
titrated[13] prior to use at 0 8C with benzoic
acid using 4-(phenylazo)diphenylamine as
the indicator. A concentration of 0.7 m in
THF was obtained.
4 c: A dry and nitrogen-flushed 10 mL
Schlenk flask equipped with a magnetic
stirring bar and a septum was charged with
a solution of 2 a (0.178 g, 1.0 mmol) in dry
THF (1 mL). Freshly prepared 3 a (0.70 m in THF, 1.57 mL, 1.1 mmol)
was added dropwise, and the reaction mixture was stirred at this
temperature for 1 h. The completion of the metalation was checked
by GC analysis of reaction aliquots quenched with a solution of I2 in
anhydrous ether. The mixture was then cooled to 40 8C, ZnCl2 (1m
solution in THF, 1.2 mL, 1.2 mmol) was added, and the reaction
mixture stirred for 15 min. [Pd(dba)2] (11 mg, 2 mol %) and P(ofuryl)3 (9 mg, 4 mol %) dissolved in THF (0.5 mL) were then transferred by cannula to the reaction mixture, and then ethyl 4iodobenzoate (0.414 g, 1.5 mmol) dissolved in THF (0.5 mL) was
added. The reaction mixture was slowly warmed to 25 8C and stirred
for 12 h. The reaction mixture was quenched with sat. aq. NH4Cl
solution, extracted with diethyl ether (3 F 15 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was removed in
vacuo. Purification by flash chromatography (n-pentane/diethyl
ether, 10:1) furnished compound 4 c (0.267 g, 82 %) as a colorless oil.
Received: April 5, 2007
Revised: May 29, 2007
Published online: July 30, 2007
Scheme 3. Preparation of 6-hexylsalicylic acid (18), a compound found
in the essential oil of Pelargonium sidoides DC.
In summary, we have reported a new class of mixed
magnesium bisamides complexed with two equivalents of
LiCl. These reagents of type (R2N)2Mg·2 LiCl 3 display
superior magnesiation capability, allowing access to new
polyfunctional aromatic or heteroaromatic reagents bearing
functional groups such as an ester, a nitrile, or a ketone.
(tmp)2Mg·2 LiCl (3 a) proves to be an especially efficient
magnesium base. Both the OBoc group and the OP(O)(NMe2)2 function serve as excellent directing groups and lead
to complementary regioselectivities. The scope of this methodology is currently being studied in our laboratories.
Experimental Section
3 a: In an argon-flushed Schlenk flask equipped with a magnetic
stirring bar, 2,2,6,6-tetramethylpiperidine (5.07 mL, 30 mmol) was
dissolved in THF (30 mL). This solution was cooled to 40 8C and
Angew. Chem. Int. Ed. 2007, 46, 7681 –7684
Keywords: copper · cross-coupling · homogeneous catalysis ·
lithium chloride · organomagnesium compounds
[1] a) M. Schlosser, Angew. Chem. 2005, 117, 380; Angew. Chem.
Int. Ed. 2005, 44, 376; b) A. Turck, N. PlH, F. Mongin, G.
QuHguiner, Tetrahedron 2001, 57, 4489; c) M. Schlosser, Eur. J.
Org. Chem. 2001, 3975; d) D. M. Hodgson, C. D. Bray, N. D.
Kindon, Org. Lett. 2005, 7, 2305; e) J.-C. Plaquevent, T. Perrard,
D. Cahard, Chem. Eur. J. 2002, 8, 3300; f) C.-C. Chang, M. S.
Ameerunisha, Coord. Chem. Rev. 1999, 189, 199; g) J. Clayden,
Organolithiums: Selectivity for Synthesis (Eds.: J. E. Baldwin,
R. M. Williams), Elsevier, Amsterdam, 2002; h) “The Preparation of Organolithium Reagents and Intermediates”: F. Leroux,
M. Schlosser, E. Zohar, I. Marek, Chemistry of Organolithium
Compounds (Eds.: Z. Rappoport, I. Marek), Wiley, New York,
2004, chap. 1, p. 435; i) M. C. Whisler, S. MacNeil, V. Snieckus, P.
Beak, Angew. Chem. 2004, 116, 2256; Angew. Chem. Int. Ed.
2004, 43, 2206; j) G. Queguiner, F. Marsais , V. Snieckus, J.
Epsztajn, Adv. Heterocycl. Chem. 1991, 52, 187; k) M. Veith, S.
Wieczorek, K. Fries, V. Huch, Z. Anorg. Allg. Chem. 2000, 626,
[2] a) R. E. Mulvey, F. Mongin, M. Uchiyama, Y. Kondo, Angew.
Chem. 2007, 119, 3876; Angew. Chem. Int. Ed. 2007, 46, 3802 –
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3824; b) K. W. Henderson, W. J. Kerr, Chem. Eur. J. 2001, 7,
3430; c) C. R. Hauser, H. G. Walker, J. Am. Chem. Soc. 1947, 69,
295; d) K. Kobayashi, T. Kitamura, R. Nakahashi, A. Shimizu, K.
Yoneda, H. Konishi, Heterocycles 2000, 53, 1021; e) M. Westerhausen, Dalton Trans. 2006, 4768.
a) P. E. Eaton, C.-H. Lee, Y. Xion, J. Am. Chem. Soc. 1989, 111,
8016; P. E. Eaton, K. A. Lukin, J. Am. Chem. Soc. 1993, 115,
11 370; T. Ooi, Y. Uematsu, K. Maruoka, J. Org. Chem. 2003, 68,
A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. 2006,
118, 3024; Angew. Chem. Int. Ed. 2006, 45, 2958; W. Lin, O.
Baron, P. Knochel, Org. Lett. 2006, 8, 5673.
For the use of ate bases see: H. Naka, M. U. Uchiyama, Y.
Matsumoto, A. E. H. Wheatley, M. McPartlin, J. V. Morey, Y.
Kondo, J. Am. Chem. Soc. 2007, 129, 1921; Y. Kondo, M. Shilai,
M. Uchiyama, T. Sakamoto, J. Am. Chem. Soc. 1999, 121, 3539;
M. Uchiyama, T. Miyoshi, T. Sakamoto, Y. Otani, T. Ohwada, Y.
Kondo, J. Am. Chem. Soc. 2002, 124, 8514; M. Uchiyama, H.
Naka, Y. Matsumoto, T. Ohwada, J. Am. Chem. Soc. 2004, 126,
10 526.
For a review of the chemistry of Li(tmp), see: M. Campbell, V.
Snieckus in Encyclopedia of Reagents for Organic Synthesis,
Vol. 5 (Ed.: L. A. Paquette), Wiley, New York, 1995. For
information on the stability of lithium amide bases in ether
solvents see: I. E. Kopka, Z. A. Fataftah, M. W. Rathke, J. Org.
Chem. 1987, 52, 448 – 450.
[7] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390.
[8] a) E. Negishi, L. F. Valente, M. Kobayashi, J. Am. Chem. Soc.
1980, 102, 3298; b) E. Negishi, M. Kobayashi J. Org. Chem. 1980,
45, 5223; c) E. Negishi, Acc. Chem. Res. 1982, 15, 340; for Pdcatalyzed Kumada – Corriu cross-coupling reactions see: R.
Martin, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129, 3844.
[9] a) F. Mongin, G. QuHguiner, Tetrahedron 2001, 57, 4059, and
references therein; b) H. Awad, F. Mongin, F. TrHcourt, G.
QuHguiner, F. Marsais, F. Blanco, B. Abarca, R. Ballesteros,
Tetrahedron Lett. 2004, 45, 6697; c) H. Awad, F. Mongin, F.
TrHcourt, G. QuHguiner, F. Marsais, Tetrahedron Lett. 2004, 45,
7873; d) T. Imahori, M. Uchiyama, T. Sakamoto, Y. Kondo,
Chem. Commun. 2001, 2450; e) P. F. H. Schwab, F. Fleischer, J.
Michl, J. Org. Chem. 2002, 67, 443.
[10] a) N. Bajwa, P. Jennings, J. Org. Chem. 2006, 71, 3646; b) For the
preparation of 14 see: S. Kamisuki, S. Takahashi, Y. Mizushina,
S. Hanashima, K. K. Kuramochi, S. Kobayashi, K. Sakagushi, T.
Nakata, F. Sugawara, Tetrahedron 2004, 60, 5695.
[11] For the preparation of 16 see: H. Ren, A. Krasovskiy, P. Knochel,
Org. Lett. 2004, 6, 4215.
[12] a) O. Kayser, K. LattP, H. Kolodziej, F.-J. Hammerschmidt,
Flavour Fragrance J. 1998, 13, 209.
[13] L. P. Hammett, G. H. Walden, S. M. Edmonds, J. Am. Chem. Soc.
1934, 56, 1092.
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7681 –7684
Без категории
Размер файла
142 Кб
using, heteroarenes, tmp, 2mg2licl, direct, magnesiation, polyfunctionalized, areneв
Пожаловаться на содержимое документа